nutrients Review Nicotinamide Riboside—The Current State of Research and Therapeutic Uses Mario Mehmel 1, Nina Jovanovi´c 2 and Urs Spitz 3,* 1 Biosynth Carbosynth, Rietlistrasse 4, 9422 Staad, Switzerland; [email protected] 2 Faculty of Biology, Department of Biochemistry and Molecular Biology, Institute of Physiology and Biochemistry, University of Belgrade, Studentski Trg 1, 11000 Belgrade, Serbia; [email protected] 3 Biosynth Carbosynth, Axis House, High Street, Compton, Berkshire RG20 6NL, UK * Correspondence: [email protected] Received: 1 May 2020; Accepted: 26 May 2020; Published: 31 May 2020 Abstract: Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NAD+ is an essential coenzyme that plays important roles in various metabolic pathways and increasing its overall content has been confirmed as a valuable strategy for treating a wide variety of pathophysiological conditions. Accumulating evidence on NRs’ health benefits has validated its efficiency across numerous animal and human studies for the treatment of a number of cardiovascular, neurodegenerative, and metabolic disorders. As the prevalence and morbidity of these conditions increases in modern society, the great necessity has arisen for a rapid translation of NR to therapeutic use and further establishment of its availability as a nutritional supplement. Here, we summarize currently available data on NR effects on metabolism, and several neurodegenerative and cardiovascular disorders, through to its application as a treatment for specific pathophysiological conditions. In addition, we have reviewed newly published research on the application of NR as a potential therapy against infections with several pathogens, including SARS-CoV-2. Additionally, to support rapid NR translation to therapeutics, the challenges related to its bioavailability and safety are addressed, together with the advantages of NR to other NAD+ precursors. Keywords: nicotinamide riboside; nicotinamide adenine dinucleotide; supplementation; safety; bioavailability; metabolic disorders; age-associated diseases; COVID-19 1. Introduction In recent years, interest in NAD+ biology has been gaining momentum, revealing critical insights into its roles in numerous physiological processes and underlining the beneficial effects of supplementation with its precursors. Moreover, accumulating evidence indicates that a decrease in NAD+ levels contributes to the development of age-associated pathophysiology [1–3]. The systemic NAD+ decrease is caused by both lowered rates of biosynthesis and increased use of NAD+. The immense demand for NAD+ is caused by its importance in cellular oxidation–reduction reactions, including the majority of catabolic and anabolic reactions, such as glycolysis, fatty acid β-oxidation, tricarboxylic acid cycle, synthesis of fatty acids, cholesterol, steroids, etc. [4–6]. Additionally, NAD+-consuming enzymes, such as sirtuins, poly-ADP-ribose polymerases (PARPs), cADP-ribose synthases (CD38/157 ectoenzymes) [7–9] and mono-ADP-ribose transferases (ARTs) contribute to an overall depletion of NAD+. Biosynthesis can compensate somewhat to the depleted levels of NAD+ via de novo synthesis from tryptophan (Trp) or in the salvage pathways from four other precursors, Nutrients 2020, 12, 1616; doi:10.3390/nu12061616 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 1616 2 of 22 nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside, and nicotinamide mononucleotide (NMN). While de novo synthesis from Trp is carried out in an eight-step pathway, the salvageable precursors NA and NAM require only three (Preiss–Handler pathway) and two steps, respectively (Figure1). Nicotinamide riboside (NR) is an additional salvageable NAD + precursor with a two-step [10] + or three-stepNutrients pathway 2020, 12, [ x11 FOR] toPEER form REVIEW NAD (Figure1). In mammals, the most common2 of 22 precursor is NAM, which can further be used to form NMN by the rate-limiting enzyme, phosphoribosyltransferase (NAMPT) [12(NMN).]. In the While final de novo step, synthesis NMN from is converted Trp is carried to out NAD in an +eight-stepby NMN pathway,/NaMN the salvageable adenylyltransferases precursors NA and NAM require only three (Preiss–Handler pathway) and two steps, respectively + (NMNATs) [(Figure13,14]. 1). Nicotinamide As a function riboside of (NR) the is aging an additional process salvageable and/or NAD overnutrition,+ precursor with aNAD two-step content and NAMPT expression[10] or three-step are found pathway to decline[11] to form in NAD multiple+ (Figure tissues 1). In mammals, [3,15– 17the], most while common the maintenanceprecursor is of NAD+ levels relies onNAM, diverse which biosynthetic can further routesbe used and to precursorsform NMN in by di fferentthe rate-limiting tissues [ 18enzyme,,19]. Nevertheless, phosphoribosyltransferase (NAMPT) [12]. In the final step, NMN is converted to NAD+ by + the decreasedNMN/NaMN expression adenylyltransferases of NAMPT enzyme (NMNATs) is [13,14]. one of As the a function major of causes the aging of process the NAD and/or decline over age [15,20]. Theovernutrition, requirement NAD+ content of this and enzymeNAMPT expression can be are bypassed found to decline with in the multiple direct tissues conversion [3,15– of NR to + NMN by two17], nicotinamide while the maintenance ribose kinases,of NAD levels NMRK1 relies andon diverse NMRK2 biosynthetic (also knownroutes and as precursors NRK1 and in NRK2) [10]. different tissues [18,19]. Nevertheless, the decreased expression of NAMPT enzyme is one of the This also circumventsmajor causes theof the requirement NAD+ decline over of energeticallyage [15,20]. The requirement costly PRPP of this (phosphoribosyl enzyme can be bypassed pyrophosphate. Figure2) andwith the the feedback direct conversion inhibition of NR to by NMN NAD by tw+o nicotinamide[21]. Alternatively, ribose kinases, NR NMRK1 can and be NMRK2 turned into NAM (also known as NRK1 and NRK2) [10]. This also circumvents the requirement of energetically costly by purine nucleoside phosphorylase (NP), which is subsequently converted to NAD+ via NMN by PRPP (phosphoribosyl pyrophosphate. Figure 2) and the feedback inhibition by NAD+ [21]. NMNAT (FigureAlternatively,1). Hence, NR thecan be utilization turned into of NAM NR by depends purine nucleoside on the expression phosphorylase of (NP), either which the is Nrk pathway or NP combinedsubsequently with the converted Nampt to pathway.NAD+ via NMN by NMNAT (Figure 1). Hence, the utilization of NR depends on the expression of either the Nrk pathway or NP combined with the Nampt pathway. Figure 1. NADFigure+ synthesis 1. NAD+ synthesis pathways. pathways. The The figure figure depicts NAD NAD+ de +novode pathway novo pathway from tryptophan from tryptophan (Trp) through quinolinic acid (QA), Preiss–Handler pathway from nicotinic acid (NA) via nicotinic (Trp) through quinolinic acid (QA), Preiss–Handler pathway from nicotinic acid (NA) via nicotinic acid acid adenine dinucleotide (NAAD) and NAD synthetase (NADS), and “salvage pathways” from adenine dinucleotidenicotinamide (NAAD) riboside and(NR) NAD and synthetasenicotinamide (NADS),mononucleotide and “salvage(NMN) via pathways” purine nucleoside from nicotinamide riboside (NR)phosphorylase and nicotinamide (NP) and mononucleotide nicotinamide phos (NMN)phoribosyltransferase via purine (NAMPT) nucleoside enzymes phosphorylase or (NP) and nicotinamidenicotinamide phosphoribosyltransferase ribose kinases (NRK) and NMN/NaMN (NAMPT) adenylyltransferases enzymes or nicotinamide (NMNAT), respectively. ribose kinases (NRK) and NMN/NaMN adenylyltransferases (NMNAT), respectively. The importance of NAD+ is reflected through the activity of NAD+-depleting enzymes, the mediators of aging, which are mostly induced by stress factors, such as DNA damage, oxidative stress, and inflammation. The major downstream mediators are sirtuins, the NAD+-dependent deacetylases/deacylases. Sirtuins are conserved regulators of aging and longevity in diverse organisms, and regarded as the master switches of metabolism [22] due to their numerous regulatory functions in metabolism, DNA repair, stress response, chromatin remodeling and circadian rhythm. (Table1)[ 2,23]. Together with sirtuins, PARPs use NAD+ to produce a chain of ADP-ribose (ADPR) molecules. PARP1 and PARP2respond to DNA breaks in the nucleus and facilitate the process of DNA repair [23]. As DNA damage accumulates over time, the activation of PARPs increase, which in turn, lowers the activity of SIRT1 due to both substrate competition and PARP20s ability to bind to the promoter of Sirt1 and repress its expression [24]. Furthermore, the content of the primary NADase in mammals, CD38, increases with age. This enzyme uses NAD+ to produce and hydrolyze the Ca2+-mobilizing Nutrients 2020, 12, 1616 3 of 22 second messenger, cADP-ribose [25–27]. CD38 can also degrade the NAD+ intermediates, NR and NMN [28,29], which further decreases the content of NAD+ [30]. The effect of CD38 on NAD+ content was demonstrated in CD38-deficient mice, whose NAD+ levels remain high. This preserves mitochondrial respiration and metabolic function with age [31]. Moreover, the inhibition of CD38 can increase NAD+ levels and improve glucose and lipid metabolism [32]. Apart from the ectoenzymes CD38 and CD157, SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing